Rheumatic diseases are a class of common diseases generally called “arthritis”, which are often associated with or caused by an autoimmune response. This class of diseases includes rheumatoid arthritis, spondyloarthropathies (e.g., ankylosing spondylitis), Sjorgren Syndrome (Sicca Syndrome), Reiter's disease, psoriatric arthritis, enteric arthritis (joint problems associated with inflammatory bowel disease), sacroiliitis or spondylitis), and osteoarthritis.
According to the Center for Disease Control (CDC), approximately 50 million adults have been diagnosed with some form of arthritis in USA alone. This number is predicted to increase to 67 million adults by 2030. The CDC estimates that the cost of arthritis in USA was approximately US$80.8 billion for treatments for arthritis and approximately US$47 billion in indirect costs (e.g., lost earnings). The total cost $127.8 billion was 1.2% of the US gross domestic product in 2003.
Rheumatoid Arthritis and Osteoarthritis
Rheumatoid arthritis (RA) is a painful chronic systemic disease characterized by extensive synovial inflammation accompanied by destruction of joint cartilage and bone. The clinical course of RA is variable and often shows a remitting pattern but if progressive inevitably leads to joint deformity and impaired function. Three forms of RA can be distinguished: mild, self-limiting disease; mildly progressive disease; and aggressive disease which is difficult to control with medication, and is characterized by functional decline and radiologic deterioration of the joints, e.g., joint space narrowing and cartilage erosions, particularly beneath the proliferating inflamed synovium referred to as pannus. In accordance with the systemic nature of the disease, there are extra-articular manifestations which include vasculitis, alveolitis, and ocular disease. Prevalence of the disease as reported in the literature is approximately 1% of the U.S. population, with women accounting for two-thirds of all cases.
The onset of RA is often insidious with fatigue, anorexia, generalized weakness, and musculoskeletal pain. Specific symptoms appear later. Several joints, usually in a symmetrical fashion, are affected. Most often these are joints of the hands, wrists, knees, and feet. Joints are painful and swollen, and motion is limited. Morning stiffness of more than one hour is a very typical finding. With persistent inflammation, a variety of deformities develop which include most typically radial deviation of the wrist and hyperextension or flexion of the proximal interphalangeal joints; other deformities occur as well. Atrophy of skeletal muscle sets in. In approximately 20 to 30% of all patients, there is development of rheumatoid nodules on periarticular structures or sites of trauma, but they are usually of limited clinical significance. The nodules may be found in other structures such as the pleura or the meninges. Rheumatoid vasculitis can affect nearly all organ systems (lung, gastro-intestinal-tract, liver, spleen, pancreas, lymph nodes, testis, and the eye).
There is no curative treatment for RA. All drug regimens primarily attempt to relieve the symptoms and the inflammation. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with a rapid onset of action are the first line of treatment. Oral and injectable glucocorticoids are added to the drug regimen if necessary. The third line of treatment includes disease modifying antirheumatic drugs (DMARDs); they have a slow onset of action, in some cases several months. DMARDs include azathioprine, sulphasalazine, gold, D-penicillamine, hydroxychloroquine, methotrexate, and cyclosporine. The more recent addition of biological drugs, such as Enbrel®, Remicade® and Humira® has provided an alternative mode of therapy, however regular use of these products can suppress the immuno defense system and has been associated with increased incidence of opportunistic infections and diseases such as tuberculosis.
Osteoarthritis (OA) is the most common form of arthritis in Western populations. Knee OA, characterized clinically by pain and functional disability, is the leading cause of chronic disability among the elderly in the US.
Pathologically, the most striking changes in OA are focal loss of articular cartilage and marginal and central new bone formation. However, OA is not simply a disease of articular cartilage and the subchondral bone. Rather, it is a disease of the synovial joint, with alterations also found in the synovium, capsule, ligaments, periarticular muscle, and sensory nerves.
Although OA was once considered a non-inflammatory arthropathy, patients often present with signs and symptoms consistent with local inflammation and synovitis, and recent evidence from preclinical and clinical studies supports the role of inflammation and inflammatory mediators in its pathophysiology.
Current treatment of osteoarthritis includes non-medicinal therapy, medicinal therapy, and surgical treatments. Non-medicinal treatments include exercise, and weightloss, programs, thermal treatment, and assistive devices or bracing. For knee OA, range-of-motion and strengthening exercises are geared toward reduction of impairment, improvement of function, and joint protection. Medications include analgesics (e.g., acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDS) that are either non-selective cyclooxygenase (COX) inhibitors or selective inhibitors of the COX-2 enzyme, injected intra-articular corticosteroids or viscosupplementation, and proven or putative disease-modifying osteoarthritis drugs (DMOADs). Surgical procedures include joint debridement and lavage, and lastly total knee arthroplasty.
The most commonly used medicinal treatments for knee OA typically provide less than 50% relief of pain. For example, use of acetaminophen, selective NSAIDs or non-selective NSAIDs typically results in mean improvements in knee OA pain of no more than 30 points from a baseline of about 70 points using 100 point (100-mm) visual analog scales. Thus, there is substantial room for improvement in the pain management of knee OA. Further, no therapy has been demonstrated to retard the progression of structural degradation.
Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a chronic, progressive, inflammatory disease with considerable impact on patient functioning, well-being, and disability. The prevalence of AS has traditionally been estimated in the range of 0.1-1.9%, with more males affected than females As a chronic disease of the axial skeleton and large peripheral joints, AS causes inflammatory back pain and stiffness and it is associated with other inflammatory diseases of the skin, eyes and intestines. In severe cases, AS may result in complete spinal fusion, causing extreme physical limitation. Thus, there remains a need for a safe and effective treatment for AS.
As the disease progresses, patients with AS experience pain, joint stiffness, and the eventual loss of spinal mobility. These clinical symptoms and subsequent disease progression result in functional limitations and impairment in health-related quality of life (HRQOL).
No cure exists for AS. Generally, treatment includes trying to relieve pain and stiffness using medications such as NSAIDs, corticosteroids, and DMARDs.
It will be apparent to the skilled artisan that inflammatory joint disease is a class of debilitating diseases having a major impact on society. There is also a need for therapeutics for these diseases.